Karjalainen MK, Holmes MV, Wang Q, et al. - Given an inverse link of circulating apolipoprotein A-I (apoA-I) levels with coronary artery disease (CAD) risk, but a lack of evidence base of this representing a causal link has led researchers to perform this study investigating the causal role of apoA-I using human genetics. They found a variant (rs12225230) in APOA1 locus that related to circulating apoA-I levels (p < 5 × 10⁻⁸) in 20,370 Finnish participants and meta-analyzed the data with a prior GWAS of apoA-I. From UK Biobank and CARDIoGRAMplusC4D, they collected genetic estimates of CAD (overall 122,733 CAD cases). They carried out a two-sample Mendelian randomization analysis. A cardioprotective role for apoA-I is not supported by the genetic evidence generated in this study. This is in line with the cumulative evidence demonstrating that a protective role of HDL-associated phenotypes in CAD is unlikely.